Subcellular Expression of Maspin in Colorectal Cancer: Friend or Foe

Abstract

In this review the authors aimed to emphasize the practical value of nuclear expression of the mammary serine protease inhibitor (maspin), also known as serpin B5 protein, in colorectal carcinoma (CRC), from pre-malignant disorders to carcinogenesis and metastasis. As the role of maspin is controversial and not yet understood, the present update highlights the latest data revealed by literature which were filtrated through the daily experience of the authors, which was gained at microscopic examination of maspin expression in CRCs and other tumors for daily diagnosis. Data regarding the subcellular localization of maspin, in correlation with the microsatellite status, grade of tumor dedifferentiation, and epithelial-mesenchymal transition (EMT) phenomenon of the tumor buds were presented with details. An original observation refers to the maspin capacity to mark the tumor cells which are “at the point of budding” that were previously considered as having “hybrid EMT phenotype”. It refers to the transitional status of tumor cell that is between “epithelial status” and “mesenchymal status”. The second original hypothesis highlights the possible role of maspin in dysregulating the intestinal microbiota, in patients with idiopathic inflammatory bowel diseases (IBD) and inducing IBD-related CRC. The dynamic process of budding and EMT of tumor buds, possible mediated by maspin, needs further investigation and validation in many human CRC samples. The histological and molecular data reveal that synthesis of maspin-based therapeutics might represent a novel individualized therapeutic strategy for patients with CRC.

Modified Tumor Budding as a Better Predictor of Lymph Node Metastasis in Early Gastric Cancer: Possible Real-World Applications

“…Tumor budding (TB) is a well-known risk factor for LNM in early-stage colorectal cancer [ 10 , 11 , 12 , 13 ]. Recently, it has also emerged as a potential predictor of LNM in gastric cancer (GC) [ 12 , 14 , 15 , 16 , 17 , 18 , 19 ].…”

From Dukes-MAC Staging System to Molecular Classification: Evolving Concepts in Colorectal Cancer

“…Our team also focused on classifying CRC based on IHC reactions and used markers of EMT such as E-cadherin, β- catenin, vimentin, and maspin, evaluated in both tumor center and invasion front/tumor buds ( Figure 2 ) [ 51 , 54 , 55 ]. We contoured three subtypes: epithelial (diffuse membrane expression of E-cadherin and β-catenin associated with negative vimentin), mesenchymal (loss of E-cadherin expression, positive vimentin and nuclear staining of β-catenin and maspin) and one with mixed epithelial-mesenchymal features called hybrid (epithelial-like pattern in the tumor center and mesenchymal characteristics in the invasion front), all of them exemplified in Figure 2 [ 51 , 56 ].…”

“…Tumor budding, defined as the single tumor cells or groups of no more than four tumor cells identified in the invasion front, represents an extensively studied parameter with a Hematoxylin-Eosin +/− cytokeratin slide-based evaluation protocol published in 2017, represents an independent prognostic marker not yet included in AJCC staging manual, but its importance and suggestion for addition in the pathological report are mentioned in oncological practice guidelines for both colon and rectal carcinomas [ 55 , 56 , 57 , 58 , 59 , 60 ]. For a better assessment of budding degree, our team used maspin’s expression which is in the nucleus at the level of the tumor buds and helps with their identification even on the background of an abundant inflammatory stroma [ 56 , 61 , 62 , 63 ].…”

“…Evaluation of subcellular maspin’s expression, combined with microsatellite status, could also be of therapeutic relevance [ 56 , 64 ]. Cytoplasmic staining identified in serrated MSI carcinomas might indicate favorable prognosis, while nuclear expression evaluated in microsatellite stable carcinomas is associated with high-grade tumor budding, EMT, mesenchymal subtype, worse prognosis, and could indicate response to therapy with fluorouracil [ 54 , 63 , 64 ].…”

Epithelial–Mesenchymal Transition Gene Signature Related to Prognostic in Colon Adenocarcinoma

“…The cell-cell contact is established by tight junctions, adherent junctions, desmosomes and gap junction, being interconnected with key signaling networks [12]. Additionally, during the EMT, the epithelial actin architecture is reorganized, observing an acquisition of cell motility and invasive features and an expression of matrix metalloproteinases (MMPs) that can destroy extracellular matrix (ECM) proteins [12][13][14] and can be affected by hypoxic condition [15]. EMT is also orchestrated by several intrinsic factors, including transcription factors or miRNAs [16,17].…”